The present invention relates to the novel process of making and purifying (+)-cis-sertraline.
Sertraline hydrochloride, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula 
is the active ingredient in Zoloft(copyright), a medication approved by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder. 
U.S. Pat. No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone. The process for synthesizing sertraline hydrochloride from sertralone comprises two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, sertraline-1-imine. 
The imine, or Schiff base, is then reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 comprises the hydrogenation of sertraline-1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereomers (xe2x80x9c(xc2x1)-cis/trans-sertralinexe2x80x9d) in the ratio of approximately 3 to 1. This hydrogenation step can introduce a number of contaminants, including dechlorinated side-products, if not carefully controlled. One very problematic group of side products are dechlorinated-sertraline derivatives. It is desirable to have a hydrogenation method that reduces the amount of dechlorinated-sertraline side products or eliminates these side products.
The purification of cis-sertraline from (xc2x1)-cis/trans-sertraline as described in the ""518 patent is relatively complicated and expensive requiring multiple recrystallizations, and the (xc2x1)-cis/trans-sertraline so produced has a cis/trans ratios lower than 3:1. It is therefore desirable to have a method of initially making cis/trans-sertraline base from sertraline-1-imine with cis/trans ratios greater than 3:1. It is also desirable to have a simple and cost effective purification of (+)-cis-sertraline from (xc2x1)-cis/trans-sertraline base or from (xc2x1)-cis/trans-sertraline hydrochloride.
The present invention relates to a process for making (xc2x1)-sertraline having a cis/trans ratio of greater than about 3:1 comprising the step of hydrogenating sertraline-1-imine at a temperature of at least about 40xc2x0 C. using a catalyst selected from the group consisting of palladium and platinum. By the processes of the present invention, catalysts include palladium on carbon, palladium on graphite, palladium on carbon paste, and PtO2.
The present invention also relates to a process for making (xc2x1)-sertraline with a cis/trans ratio between about 8:1 and about 12:1 comprising the step of hydrogenating sertraline-1-imine at a temperature of at least about 40xc2x0 C. using a palladium catalyst. By the processes of present invention, suitable catalysts include, palladium on carbon, palladium on graphite, and palladium on carbon paste.
The present invention also relates to a process for making (+)-cis-sertraline hydrochloride comprising the step of reacting an optically active selective precipitant with (xc2x1)-sertraline base having a cis/trans ratio of greater than 3:1.
The present invention also relates to a process for making (+)-cis-sertraline which is substantially free of dechlorinated side products, comprising the step of catalytically hydrogenating sertraline-1-amine using PtO2 as a catalyst.
The present invention also relates to a process for making (+)-cis-sertraline hydrochloride from (xc2x1)-sertraline hydrochloride with a cis/trans ratio of greater than 3:1 comprising the steps of: generating (xc2x1)-sertraline by addition of an aqueous base to (xc2x1)-sertraline hydrochloride with a cis/trans ratio of greater than 3:1; resolving the (xc2x1)-sertraline so generated; and isolating (+)-cis-sertraline hydrochloride.
The present invention also relates to a process for making (+)-cis-sertraline hydrochloride from (xc2x1)-sertraline hydrochloride comprising the steps of: generating (xc2x1)-sertraline by addition of a solid base to (xc2x1)-sertraline hydrochloride; resolving the (xc2x1)-sertraline so generated; and isolating (+)-cis-sertraline hydrochloride.
The present invention also relates to a process for making (+)-cis-sertraline from (xc2x1)-sertraline base wherein the (xc2x1)-sertraline base has a content of dechlorinated-sertraline side products that is very low, e.g., less than about 1%, or alternatively, wherein the content of dechlorinated-sertraline side products is undetectable by conventional methods, comprising the steps of: generating (xc2x1)-sertraline by addition of a solid base to (xc2x1)-sertraline hydrochloride; resolving the (xc2x1)-sertraline so generated; and isolating (xc2x1)-cis-sertraline hydrochloride.